Systems and methods for reducing skull-induced thermal aberrations during transcranial ultrasound therapy procedures

Abstract

Various example embodiments of the present disclosure provide systems and methods for dynamic correction and reduction of thermal changes in skull-induced aberrations in focused ultrasound treatment procedures. Unlike conventional approaches that involve static correction of skull-induced aberrations, various example embodiments of the present disclosure employ ultrasound detection and skull thickness estimation from volumetric image data to intermittently and dynamically determine correction of skull-induced aberrations such that, despite local heat-induced changes in sound speed in local skull regions due to intraoperative intracranial heating, the aberration correction is reduced and maintained intraoperatively. Furthermore, in some example embodiments, a measure dependent on skull sound speed is determined intraoperatively and compared to a pre-determined measurement to determine a change in skull temperature based on a pre-determined relationship between the measure change and skull temperature change.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 855,283, filed May 31, 2019, entitled “SYSTEMS AND METHODS FOR REDUCING THERMAL SKULL-INDUCED ABERRATIONS DURING TRANSCRANIAL ULTRASOUND THERAPEUTIC PROCEDURES”, the entire contents of which are incorporated herein by reference. Background Technology

[0003] This disclosure relates to ultrasound-based therapy and imaging. More particularly, this disclosure relates to transcranial ultrasound systems and methods.

[0004] Transcranial focused ultrasound (FUS) therapy has emerged as a potential alternative to traditional surgery due to its ability to non-invasively ablate targets deep within the brain. Currently, this technology has been successfully adopted and studied in clinical thermal ablation of small targets for essential tremor (Elias et al. 2013, Lipsman et al. 2013, Elias et al. 2016), brain tumors (McDannold et al. 2010, Coluccia et al. 2014), obsessive-compulsive disorder (Jung et al. 2015), chronic neuropathic pain (Martin et al. 2009, Jeanmonodet et al. 2012), and depression (Kim et al. 2018). Treatment for essential tremor received regulatory approval from multiple regulatory agencies, including the U.S. Food and Drug Administration, in 2016.

[0005] Clinical implementation of transcranial FUS requires accurate and precise localization through the entire skull, which is challenging due to the skull's inhomogeneities (Clement and Hynynnen 2002a), leading to distorted brain focus (Fry and Barger 1978). Therefore, various methods have been proposed to correct for this aberration. For example, the ultrasound imaging time-shift method is used by calculating the time delay corresponding to the peak of the cross-correlation between signals from adjacent transducers (Flax and O'Donnell 1988, O'Donnell and Flax 1988, Nocl, Trahey and Smith 1989). Later, Thomas and Fink (Thomas and Fink 1996) and Tanter et al. (Tanter, Thomas and Fink 1998) employed a time-reversal mirror. In short, ultrasound is emitted from a transducer implanted at the desired treatment volume. A treatment array is applied to record the waves and re-emit them to the target of the implanted transducer. Meanwhile, corrections for catheter-based hydrophones for the liver (Seip, VanBaren and Ebbini 1994) and brain (Aubry et al. 2001, Clement and Hynynnen 2002b) were proposed.

[0006] These methods have shown feasibility in improving focusing quality, but require initial invasive implantation of the transducer. To achieve non-invasive transcranial therapy, it has been found that skull aberration correction can be performed non-invasively using skull density and thickness information obtained from preoperative CT images that enable clinical brain therapy (Clement and Hynynen 2002c). Several computer models using CT information have since been developed, demonstrating the ability to achieve cross-skull focusing (Aubry et al. 2003, Jones, O'Reilly, and Hynynen 2015).

[0007] Many clinical implementations of transcranial focused ultrasound (TCU) therapy employ accurate and precise targeting through the entire skull, which is challenging due to the skull's inhomogeneities (Clement and Hynynnen 2002a), leading to distorted brain focus (Fry and Barger 1978). Therefore, various methods have been proposed to correct for this aberration. For example, the ultrasound imaging time-shift method has been used by calculating the time delay corresponding to the peak of the cross-correlation between signals from adjacent transducers (Flax and O'Donnell 1988, O'Donnell and Flax 1988, Nocl, Trahey, and Smith 1989). Later, Thomas and Fink (Thomas and Fink 1996) and Tanter et al. (Tanter, Thomas, and Fink 1998) employed a time-reversal mirror. In short, ultrasound is emitted from a transducer implanted at the desired treatment volume. A treatment array is applied to record the waves and re-emit them to the target of the implanted transducer. Meanwhile, corrections based on catheter-inserted hydrophones have been proposed for the liver (Seip, VanBaren, and Ebbini 1994) and the brain (Aubry et al. 2001, Clement and Hynynnen 2002b). These methods have shown feasibility in improving focusing quality, but require initial invasive implantation of the transducer.

[0008] To achieve non-invasive transcranial therapy, it was discovered that skull aberration correction can be performed non-invasively using skull density and thickness information obtained from preoperative CT images (Clement and Hynynen 2002c) that make clinical brain therapy feasible. Several computer models using CT information have since been developed, demonstrating the ability to achieve cross-skull focusing (Aubry et al. 2003, Jones, O'Reilly, and Hynynen 2015). CT information can also be used to design acoustic lenses with controlled thickness coupled to single-element transducers for transcranial applications (e.g., G. Maimbourg, A. Houdouin, T. Deffieux, M. Tanter, and J. Faubry, "3D-printed adaptive acoustic lens as a disruptive technology for transcranial ultrasound therapy using single-element transducers," Phys Med Biol, Vol. 63, No. 2, pp. 025026, January 16, 2018; and G. Maimbourg, A. Houdouin, T. Deffieux, M. Tanter, and J. Faubry, "Steering capabilities of anacoustic lens for transcranial therapy: numerical and experimental studies," IEEE Trans Biomed Eng, March 26, 2019).

[0009] A method based on the resonant frequency of material thickness has been proposed (Ohkawai 1983, Guyott 1988) for measuring phase shifts induced by the skull (Aarnio et al. 2005). In Aarnio's study, pulses were emitted using a broadband ultrasound transducer, and reflected acoustic signals from the inner and outer surfaces of the skull were recorded. Spectral analysis was then performed to extract the resonant frequency of the skull. Furthermore, direct measurement of skull thickness using calipers or micrometers is not feasible in practical clinical applications. Invention Overview

[0011] Various exemplary embodiments of this disclosure provide systems and methods for the dynamic correction and reduction of thermal changes in skull-induced aberrations during focused ultrasound treatment procedures. Unlike conventional methods involving static correction of skull-induced aberrations, the various exemplary embodiments of this disclosure employ ultrasound detection and skull thickness estimation from volumetric imaging data to intermittently and dynamically determine corrections for skull-induced aberrations, such that aberration correction reductions are updated and maintained intraoperatively, despite local thermally induced changes in the velocity of sound in local skull regions due to intraoperative intracranial heating. Furthermore, in some exemplary embodiments, a metric dependent on skull velocity of sound is determined intraoperatively and compared with a predetermined value of the metric to determine changes in skull temperature based on a predetermined relationship between metric changes and changes in skull temperature.

[0012] Therefore, in a first aspect, a method for reducing skull-induced aberrations during intraoperative intracranial focused ultrasound treatment procedures is provided, the method comprising:

[0013] After starting to use an array of ultrasonic transducers to deliver focused ultrasound to the object:

[0014] a) The array of ultrasonic transducers is used to transmit non-therapeutic ultrasonic pulses and receive reflected ultrasonic pulses, thereby obtaining a received signal;

[0015] b) Determine a correction for calibrating the treatment transmission signal delivered to the ultrasound transducer during subsequent focused ultrasound treatment, wherein the correction is adapted to reduce cranial evoked aberrations associated with a local cranial region adjacent to the ultrasound transducer, wherein the correction is determined by processing the received signal and employing a cranial thickness estimate associated with the local cranial region, and wherein the cranial thickness estimate is obtained based on previously measured object-related volumetric image data; and

[0016] c) Repeat steps a) and b) once or more during the intracranial focused ultrasound treatment procedure to intermittently recalculate the correction and thus maintain the reduction in aberrations, despite the local thermally induced changes in the velocity of sound in the local cranial region due to intracranial heating during the procedure.

[0017] In another aspect, a method is provided for reducing skull-induced aberrations during intraoperative intracranial focused ultrasound treatment procedures, the method comprising:

[0018] After starting to use an array of ultrasonic transducers to deliver focused ultrasound to the object:

[0019] a) The ultrasonic transducer of the array is used to transmit ultrasonic energy and receive reflected ultrasonic energy, thereby obtaining a received signal related to the reflected ultrasonic energy.

[0020] b) Determine a correction for calibrating the treatment transmission signal delivered to the ultrasound transducer during subsequent focused ultrasound treatment, wherein the correction is adapted to reduce cranial evoked aberrations associated with local cranial regions adjacent to the ultrasound transducer, wherein the correction is determined by processing the received signal and employing a cranial thickness estimate associated with the local cranial region, and wherein the cranial thickness estimate is obtained based on previously measured object-related volumetric image data; and

[0021] c) During subsequent delivery of focused ultrasound to the subject, a correction is applied to the therapeutic transmission signal provided to the ultrasound transducer to reduce skull-induced aberrations; and

[0022] d) Repeat steps a) through c) once or more during the intracranial focused ultrasound treatment procedure to intermittently recalculate the corrections and thus maintain the accuracy of aberration corrections, despite local thermally induced changes in the velocity of sound in the local skull area due to intracranial heating during the procedure.

[0023] On the other hand, a method is provided for intraoperatively controlling an intracranial ultrasound therapy system to reduce skull-induced aberrations during intracranial focused ultrasound therapy procedures, the intracranial ultrasound therapy system comprising an array of ultrasound transducers and associated transducer drive circuitry, the method comprising:

[0024] After the array of focused ultrasound transducers begins delivering focused ultrasound to the object:

[0025] a) The array of ultrasonic transducers is used to transmit non-therapeutic ultrasonic pulses and receive reflected ultrasonic pulses, thereby obtaining a received signal;

[0026] b) Determine a correction for calibrating the treatment transmission signal delivered to the ultrasound transducer during subsequent focused ultrasound treatment, wherein the correction is adapted to reduce cranial evoked aberrations associated with local cranial regions adjacent to the ultrasound transducer, wherein the correction is determined by processing the received signal and employing a cranial thickness estimate associated with the local cranial region, and wherein the cranial thickness estimate is obtained based on previously measured object-related volumetric image data; and

[0027] c) Control the transducer drive circuit so that when focused ultrasound therapy is subsequently delivered to the subject during an intracranial focused ultrasound therapy procedure, a correction is applied to the transmission signal provided to the ultrasound transducer; and

[0028] d) Repeat steps a) through c) once or more during the intracranial focused ultrasound treatment procedure to intermittently recalculate the correction and thus maintain the reduction in aberrations, despite the local thermally induced changes in the velocity of sound in the local skull area due to intracranial heating during the procedure.

[0029] On the other hand, a method for performing an intracranial focused ultrasound treatment procedure is provided, the method comprising:

[0030] An array of ultrasonic transducers is used to deliver focused ultrasound to an object;

[0031] a) The ultrasonic transducer of the array is used to transmit ultrasonic energy and receive reflected ultrasonic energy, thereby obtaining a received signal related to the reflected ultrasonic energy.

[0032] b) Determine a correction for calibrating the treatment transmission signal delivered to the ultrasound transducer during subsequent focused ultrasound treatment, wherein the correction is adapted to reduce cranial evoked aberrations associated with local cranial regions adjacent to the ultrasound transducer, wherein the correction is determined by processing the received signal and employing a cranial thickness estimate associated with the local cranial region, and wherein the cranial thickness estimate is obtained based on previously measured object-related volumetric image data; and

[0033] c) Deliver focused ultrasound therapy to the subject while applying corrections to the treatment transmission signal to reduce skull-induced aberrations; and

[0034] d) Repeat steps a) through c) once or more during the intracranial focused ultrasound treatment procedure to intermittently recalculate the correction and thus maintain the reduction in aberrations, despite the local thermally induced changes in the velocity of sound in the local skull area due to intracranial heating during the procedure.

[0035] In another aspect, a method for measuring skull temperature changes during intracranial focused ultrasound treatment procedures is provided, the method comprising:

[0036] a) A first received signal is obtained by transmitting a first non-therapeutic ultrasound pulse and receiving a first reflected ultrasound pulse using an ultrasound transducer located near the skull of the object.

[0037] b) After delivering focused ultrasound to the object, a second non-therapeutic ultrasound pulse is transmitted and a second reflected ultrasound pulse is received using an ultrasound transducer, thereby obtaining a second received signal;

[0038] c) Process the first received signal to determine a first value of a metric that depends on the speed of sound in the skull;

[0039] d) Process the second received signal to determine a second value for a metric dependent on the speed of sound in the skull; and

[0040] e) The change in skull temperature is determined using a first value of the measurement, a second value of the measurement, and a predetermined correction between skull temperature and the change in the measurement.

[0041] On the other hand, an intracranial focused ultrasound treatment system is provided, comprising:

[0042] Array of ultrasonic transducers;

[0043] A transducer drive circuit operatively coupled to an array of said ultrasonic transducers; and

[0044] A control and processing circuit, operably coupled to a transducer drive circuit, includes at least one processor and an associated memory storing instructions executable by the at least one processor to perform operations including:

[0045] After initiating the delivery of focused ultrasound to the object using the array of ultrasound transducers in a focused ultrasound therapy procedure:

[0046] a) The array of ultrasonic transducers is used to transmit non-therapeutic ultrasonic pulses and receive reflected ultrasonic pulses, thereby obtaining a received signal;

[0047] b) Determine a correction for calibrating the treatment transmission signal delivered to the ultrasound transducer in subsequent focused ultrasound therapy, wherein the correction is adapted to reduce cranial evoked aberrations associated with local cranial regions adjacent to the ultrasound transducer, wherein the correction is determined by processing the received signal and employing a cranial thickness estimate associated with the local cranial region, and wherein the cranial thickness estimate is obtained based on previously measured object-related volumetric image data; and

[0048] c) Controlling the transducer drive circuit to apply a correction to the transmission signal provided to the ultrasound transducer when delivering focused ultrasound therapy to the subject during subsequent intracranial focused ultrasound therapy procedures; and

[0049] d) Repeat steps a) through c) once or more during the intracranial focused ultrasound treatment procedure to intermittently recalculate the correction and thus maintain the reduction in aberrations, despite the local thermally induced changes in the velocity of sound in the local skull area due to intracranial heating during the procedure.

[0050] On the other hand, a method for reducing aberrations in intracranial focused ultrasound treatment procedures is provided, the method comprising:

[0051] An array of ultrasonic transducers is used to transmit non-therapeutic ultrasonic pulses and receive reflected ultrasonic pulses, thereby obtaining a received signal.

[0052] Process the received signal to determine if one or more metrics associated with the received signal meet exclusion criteria; and

[0053] No ultrasound transducer is used during the subsequent delivery of focused ultrasound therapy via the array.

[0054] A further understanding of the function and advantages of this disclosure can be achieved by referring to the following detailed description and accompanying drawings.

[0055] Brief description of the attached figures

[0056] The implementation scheme will now be described with reference to the accompanying drawings, by way of example only, wherein:

[0057] Figure 1A This is a flowchart illustrating an example method for reducing skull-induced aberrations during intraoperative focused ultrasound treatment procedures.

[0058] Figure 1B This is a flowchart illustrating an example method for tracking changes in skull temperature during intraoperative intracranial focused ultrasound treatment.

[0059] Figure 2 An example system for performing transcranial diagnostic and / or therapeutic procedures is shown.

[0060] Figure 3A A cross-sectional illustration of a sample patient-specific head assembly used for transcranial treatment procedures is shown.

[0061] Figure 3B An exemplary embodiment is shown in which transcranial ultrasound transducer array elements are supported relative to the skull by a support frame, wherein ultrasound beams are emitted from the transcranial ultrasound transducer array elements such that they are individually defocused in the far field while overlapping in the far field to produce focus.

[0062] Figure 3C An exemplary embodiment is shown, which illustrates the positioning and focusing of transcranial ultrasound transducer array elements relative to the skull, such that the focus of the transcranial ultrasound transducer array elements is located within the skull.

[0063] Figure 3D The wavefronts from multiple transcranial ultrasound transducer array elements are shown to be focused in the far field.

[0064] Figure 4A An example process for designing and constructing a patient-specific array for transcranial focused ultrasound therapy is shown.

[0065] Figure 4B This is a flowchart illustrating an example method for manufacturing patient-specific head components.

[0066] Figure 5 This is a schematic diagram of the experimental setup for pulse-echo measurement based on the resonance method and hydrophone measurement.

[0067] Figures 6A to 6C Depicting ( Figure 6A The radio frequency (RF) signal measured in the time domain; Figure 6B ) The spectrum available within the bandwidth (0.3-0.8MHz); and ( Figure 6C The spectrum of deconvolution.

[0068] Figures 7A to 7D Depicting ( Figure 7A Phase shift calculated using a resonance-based method as a phase shift function for hydrophone measurement; Figure 7BHistogram of the phase difference of Sk1-4 skull caps; Figure 7C The phase shift calculated from the reflection of the phase shift function measured by the hydrophone; and ( Figure 7D Histogram of the phase difference of the skull cap Sk1-4, excluding measurement points with an incident angle ≥5°. Solid and dashed lines represent phase differences of 0° and ±45° between the two modes, respectively.

[0069] Figures 8A to 8D Depicting ( Figure 8A ) CT-based phase shift as a phase shift function measured by hydrophone; Figure 8B Histogram of the phase difference of Sk1-4 skull caps; Figure 8C ) as a phase shift function measured by hydrophones, based on CT; and ( Figure 8D Histogram of the phase difference of the skull cap Sk1-4, excluding measurement points with an incident angle ≥5°. Solid and dashed lines represent phase differences of 0° and ±45° between the two modes, respectively.

[0070] Figures 9A to 9B The cumulative proportion of phase difference for all measurement points in the three modes (solid line: resonance relative to the hydrophone method; dashed line: CT-based correction relative to the hydrophone method) is depicted, showing ( Figure 9A All four skulls are indicated by red lines, and cases with an incident angle less than 5° are indicated by blue lines, and ( Figure 9B Skull bones 1-4 are represented by black, red, blue, and magenta lines respectively. Evenly distributed bones are indicated by dashed lines. Ideally, this graph would be a step function.

[0071] Figures 10A to 10B Depicting ( Figure 10A Average time delay and ( Figure 10B Comparison of the speed of sound in the skull (n=403) calculated from hydrophone and resonance methods. “AllSk” represents the average time delay and speed of sound for all four skulls.

[0072] Figures 11A to 11B Depicting ( Figure 11A A summary of phase shift changes measured on all four skulls using resonance and hydrophone methods. Figure 11B The change in the skull resonant frequency as a function of temperature.

[0073] Figure 12 The table provides values ​​for the average thickness, angle of incidence, and percentage of phase difference (n) at less than 45° and 20° on skull 1–4 for all measurement points. 总 =784). Invention Details

[0075] Various embodiments and aspects of this disclosure will be described with reference to the details of the following discussion. The following description and figures are illustrative of this disclosure and should not be construed as limiting it. Numerous specific details are described to provide a thorough understanding of the various embodiments of this disclosure. However, in some cases, well-known or conventional details have not been described in order to provide a concise discussion of embodiments of this disclosure.

[0076] As used herein, the terms “comprises” and “comprising” should be interpreted as inclusive and open-ended, not exclusive. Specifically, when used in the specification and claims, the terms “comprises” and “comprising” and their variations mean to include the specified features, steps, or components. These terms should not be construed as excluding the presence of other features, steps, or components.

[0077] As used herein, the term “exemplary” means “used as an example, illustration or illustration” and should not be construed as superior to or advantageous to other configurations disclosed herein.

[0078] As used herein, the terms “about” and “approximately” are intended to cover possible variations within the upper and lower limits of the value range, such as variations in properties, parameters, and dimensions. Unless otherwise stated, the terms “about” and “approximately” mean plus or minus 25% or less.

[0079] It should be understood that, unless otherwise stated, any specified scope or group refers individually, in a simplified manner, to each member of the scope or group, and to each possible subscope or subgroup included therein, and similarly with respect to any subscope or subgroup therein. Unless otherwise stated, this disclosure relates to and explicitly includes combinations of each particular member and subscope or subgroup.

[0080] As used herein, the term "on the order of" when used in conjunction with a quantity or parameter refers to a range spanning approximately one-tenth to ten times the quantity or parameter.

[0081] As mentioned above, several previous studies have addressed the need to compensate for skull-induced phase aberrations during intracranial focused ultrasound therapy. It is also known (Clement and Hynynnen 2002a) that skull-induced phase shifts are largely insensitive to temperature. In fact, Clement and Hynynnen state that "phase measurements taken at room temperature can be used for phase correction through the skull at body temperature," and that "an increase in skull temperature (~10°C) during therapeutic treatment should not significantly alter the phase."

[0082] Having demonstrated a negative correlation between power and acoustic efficiency through experiments, and given the positive correlation between power and skull heating, the inventors suspect that previous conclusions in the art regarding the effect of temperature on skull-induced phase aberrations may be incorrect. In fact, the inventors suspect that, as observed in their experiments, skull heating leads to an increase in focal spot size and a decrease in heating efficiency for clinical brain therapy, and hypothesize that the limitation on focal temperature rise at higher power may be due to a decrease in heating efficiency caused by focal length widening resulting from incorrect temperature correction dependent on skull-induced aberrations. Therefore, the inventors suspect that this focal length widening may be due to a failure to compensate for changes in skull sound velocity caused by spatially uneven increases in skull temperature.

[0083] Recognizing this technical problem in the field of intracranial focused ultrasound therapy, the inventors sought to develop a solution to reduce thermally induced changes in skull-induced aberrations during focused ultrasound therapy procedures.

[0084] As explained in the embodiments provided below, the inventors conducted a series of experiments that, in stark contrast to the teachings and biases previously presented by Clement and Hynynnen 2002a, demonstrated a strong dependence of cranial induced aberrations on cranial temperature. For example, measurements of cranial induced phase shifts as the temperature increased from 25°C to 42°C were performed using resonance and hydrophone methods (described in detail below). It was found that the cranial induced phase shifts from four example cranial samples, measured between room temperature and 42°C as a function of temperature (at a center frequency of 0.5 MHz), changed significantly as a function of temperature, with a phase transition of 2.65°C per degree Celsius. Furthermore, the inventors also found that the variation in the measured mean resonant frequency of the cranium was inversely proportional to the variation in temperature.

[0085] The inventors concluded from these experimental findings that a significant increase in intracranial temperature is expected during high-intensity transcranial therapeutic ultrasound procedures, contrary to conventional knowledge in the art. This leads to significant changes in skull density and sound velocity, and consequently, significant cranial induced phase shifts that can affect the efficiency and accuracy of focused ultrasound therapy. Therefore, methods were determined to correct for the dynamic, intraoperative, and spatial heterogeneity (transducer-specific) of thermally induced changes that promote cranial induced aberrations.

[0086] Various exemplary embodiments of this disclosure provide systems and methods for dynamically correcting and reducing thermal changes in skull-induced aberrations during focused ultrasound (FUS) treatment procedures. Unlike conventional methods where static corrections for skull-induced aberrations are determined preoperatively, these exemplary embodiments, applied before the start of FUS treatment and subsequently without modification during the procedure, employ ultrasound detection and skull thickness estimated from volumetric imaging data to intermittently and dynamically determine corrections for skull-induced aberrations during FUS treatment procedures. This allows aberration correction reductions to be updated and maintained intraoperatively, despite local thermally induced changes in the velocity of sound in local skull regions due to intraoperative intracranial heating. Furthermore, in some exemplary embodiments, a metric dependent on skull velocity is determined intraoperatively and compared to a predetermined metric to determine changes in skull temperature based on a predetermined relationship between metric changes and changes in skull temperature.

[0087] In one example implementation, a method is provided in which the ultrasound transducers of a transcranial ultrasound array are used to intermittently detect ultrasound energy reflected from the skull to non-invasively monitor local skull heating. As explained in detail below, the ultrasound transducers of the transcranial ultrasound array are intermittently employed in a focused ultrasound treatment procedure to detect reflected ultrasound energy reflected from a local skull region adjacent to the transducers, and the detected signals are processed and combined with a volumetric image-based estimate of local skull thickness to determine a dynamic correction for adjusting the phase of the drive signal to compensate for heating-induced variations. This dynamic correction can be calculated intermittently (e.g., periodically or irregularly) during the focused ultrasound treatment procedure. Furthermore, the dynamic correction can be determined and applied to multiple ultrasound transducers of the array, such as all ultrasound transducers in the array.

[0088] The exemplary methods and systems described herein can improve the accuracy, efficiency, and quality of intracranial focused ultrasound (ICU) treatment procedures. Furthermore, this exemplary implementation may enhance the feasibility of some ICU treatment procedures that would otherwise be considered infeasible due to heating effects. Indeed, despite the success of some clinical trials involving ICU, many patients still cannot reach sufficient temperatures for thermal ablation. Moreover, in some cases, ICU treatment procedures are considered infeasible because the skull temperature becomes extremely high during procedures that could induce skull injury. Additionally, in some clinical cases, only the central target can be treated due to excessive skull heating. The improved treatment efficiency achievable according to the exemplary implementation described herein can effectively reduce the degree of skull heating in such procedures, thereby increasing their potential feasibility.

[0089] Now for reference Figure 1AAn example method is provided for reducing skull-induced aberrations during intraoperative intracranial focused ultrasound treatment procedures. After delivering focused ultrasound to the subject using an array (100) of ultrasound transducers, the array's ultrasound transducers are used to transmit non-therapeutic ultrasound pulses to local areas of the skull adjacent to the ultrasound transducers and to receive reflected ultrasound pulses, thereby obtaining a received signal, as shown in step 105.

[0090] As used herein, the phrase "non-therapeutic" refers to a pulse with energy lower than that used by the ultrasound transducer during the delivery of focused ultrasound therapeutic energy, wherein the non-therapeutic ultrasound pulse is used to measure ultrasound energy reflected from the skull, in contrast to delivering ultrasound energy to an intracranial target to produce a therapeutic effect. In some example embodiments, the non-therapeutic ultrasound pulse may have a bandwidth exceeding that of the ultrasound pulse used in focused ultrasound therapeutic delivery, allowing the reflected signal to be processed to accurately determine the resonant characteristics of the reflected pulse spectrum and / or determine the time of flight of the reflected pulse. In some example embodiments, the non-therapeutic ultrasound pulse, which may alternatively be referred to as a "diagnostic" ultrasound pulse, may have a bandwidth of at least 500 kHz. In some exemplary embodiments, the center frequency range of the non-therapeutic ultrasound pulse may be from 0.5 MHz to 15 MHz.

[0091] The received signal is then processed, as shown in 110, together with an estimate of the local skull thickness obtained from the processing of volumetric image data associated with the object, to determine the corrections used to calibrate the therapeutic transmission signals delivered to the ultrasound transducer in subsequent focused ultrasound therapy.

[0092] The calculation correction makes it suitable for reducing or substantially eliminating cranial induced aberrations associated with localized cranial regions adjacent to the ultrasound transducer. For example, the correction could be a phase correction used to adjust the phase of the transmitted signal delivered to the ultrasound signal during subsequent focused ultrasound energy delivery. In another example embodiment, the correction could be a time delay used to delay the delivery of the transmitted signal. Various non-limiting examples of suitable corrections and their applications are described in further detail below.

[0093] like Figure 1A As shown in 120, steps 105 and 110 can be repeated for one or more ultrasonic transducers in the array. In one example embodiment, the calibration is calculated for all ultrasonic transducers in the array. In another example embodiment, the calibration can be calculated for a subset of the ultrasonic transducers in the array.

[0094] These steps can then be repeated once or multiple times in the intracranial focused ultrasound treatment procedure (115), as shown in 125, to intermittently recalculate corrections and thus maintain aberration reduction, despite local thermally induced changes in the velocity of sound in the local cranial region due to intracranial heating during the procedure. Figure 1AThe corrections calculated after the start of focused ultrasound treatment (100) are shown, and will be understood. Figure 1A This is not intended to be restrictive, and corrections can be calculated before the start of focused ultrasound treatment (e.g., initial corrections can be calculated for the initial phase of focused ultrasound treatment before perceptible skull heating).

[0095] The following provides a non-limiting example of calculating the correction for a given ultrasound transducer. According to this example, the correction can be calculated by first processing the received signal obtained from the detected ultrasound pulse reflections, wherein the processing is performed in the frequency domain to identify resonances associated with local cranial regions adjacent to the ultrasound transducers.

[0096] The spectrum of the reflected signal from a broadband pulse in a lossy medium produces a result similar to that of the intensity transmission coefficient:

[0097]

[0098] Where ρ, c, k b Let and d represent density, speed of sound (SoS), wavenumber, and thickness, respectively, and the subscripts b and w represent the propagation medium bone and water, respectively. From equation (1), it is clear that when k b At frequencies of d = nπ, total transmission occurs, which manifests as a reduction in reflections from the skull across the spectrum of the reflected signal. These minimum frequencies are the resonant frequencies of the bone layers and can be obtained by locating the zero point of the first derivative relative to the frequency.

[0099]

[0100] From equation (2), the SoS in bone can be calculated as follows:

[0101] c b =2d(f i+1 -f i )=2dΔf。 (3)

[0102] The time delay caused by skull insertion can be expressed as

[0103]

[0104] The equation that generates the phase difference caused by the skull is:

[0105]

[0106] Where f represents the center frequency of the transducer, and SoS in water is c w It is temperature-dependent, and d is the skull thickness at the target point, which may be obtained from volumetric image data related to the object (such as preoperative computed tomography images), as further described below.

[0107] After recording the signal (echo) reflected from the skull surface, a Fourier transform can be applied, followed by deconvolution of the transducer's pulse response. The phase shift can then be calculated using the resonant characteristics in the spectrum. In the embodiment provided below, the phase shift is calculated using local minima within the transducer bandwidth (0.3–0.8 MHz), and averaged at each point. The results are compared to the gold-standard hydrophone method, where the waveform is digitally filtered using a fourth-order Butterworth bandpass filter (0.1–1 MHz), and the time-of-flight variation is calculated by cross-correlation of data with and without the skull.

[0108] Local thickness of the skull can be calculated from volumetric image data, such as computed tomography (CT) or magnetic resonance imaging (MRI). An example method for calculating local skull thickness using preoperative CT image data is provided in the Examples section below.

[0109] Volumetric image data can be converted from a volumetric imaging system reference frame to an intraoperative reference frame by applying appropriate transformations to facilitate the determination of effective skull thickness estimates for local skull regions adjacent to ultrasound transducers. For example, skull registration can be achieved via ultrasound-based methods as described in O'Reilly et al., 2016. In short, the transducer is excited one pulse at a time in a single-cycle pulse train. Signals reflected from the outer surface of the skull are recorded, and the distance to a point on the skull is calculated from the time of flight using the first echo. The outer surface of the skull is segmented from CT data and defined by a series of vertices and faces. Given CT and ultrasound data, the skull location can then be solved using nearest-point-based methods (e.g., Besl and McKay, 1992), and registration can be determined.

[0110] Although this example implementation involves calculating phase transition correction, it will be understood that the correction may alternatively be calculated based on another metric such as time delay.

[0111] Furthermore, while the preceding example implementations involve calculating corrections based on the analysis of resonance characteristics in the spectrum of the received signal, it is understood that other methods of processing the received signal may alternatively be used when determining the corrections.

[0112] For example, in an alternative embodiment, time-domain analysis can be performed using a pulse-echo analysis method. The arrival times of the first and second echoes are denoted as t1 and t2, respectively. The propagation time delay through the local cranial region can be expressed as Δt = (t2 - t1) / 2, resulting in a phase shift. This time delay is the net time delay propagating through the skull. The time offset correction (from the time delay of cranial insertion) caused by the disturbance Δt due to the presence of bone rather than water can then be calculated as Δt. 脉冲-回波 =d / c bTherefore, the time delay for skull insertion is t = d / c b -d / c w =Δt 脉冲-回波 -d / c w It can be calculated using the local skull thickness estimated from processed volumetric image data. It will be understood that a time-domain approach should be used with a non-therapeutic ultrasound pulse having a duration less than the flight time of the intracranial round-trip journey.

[0113] It will be understood that the array of ultrasonic transducers can be single-element or multi-element ultrasonic transducers, such as a single focusing transducer element or a phased array. In some example implementations, the ultrasonic transducers can be configured to achieve intracranial focusing (examples of such configurations are provided below).

[0114] As explained in the following embodiments section, the inventors have discovered that this exemplary alignment method achieves excellent performance when the ultrasonic transducers of the array are positioned such that their respective beam axes are perpendicular to the skull surface. This alignment can be achieved, for example, using a phased array configuration of ultrasonic elements and electron beam manipulation, such that normal incidence is achieved when the sum of the peak values ​​in the reflected signals received by each element in the phased array reaches its maximum value. In an alternative exemplary embodiment, the angle of a single element transducer can be varied until maximum echo is received from the skull surface. The transducer angle variation can be performed, for example, mechanically (using single element transducers) or electrically (using phased array transducers).

[0115] In some example implementations, the received signal can be used to identify one or more abnormal transducers in the array and to avoid using one or more abnormal transducers during focused ultrasound therapy, thus preventing the use of specific ultrasound transducers that could jeopardize the ability to achieve accurate intracranial focusing. For example, exclusion criteria can be developed so that if one or more metrics obtained by processing the received signal of a given ultrasound transducer are satisfactory, that transducer will not be used during subsequent focused ultrasound therapy. The measurement of the received signal and the assessment of whether one or more metrics meet the exclusion criteria can be performed before or after the start of focused ultrasound therapy.

[0116] In one example implementation, exclusion criteria may involve comparing one or more metrics related to the signal-to-noise ratio (SNR) of the spectrum with pre-established thresholds. In another example implementation, a given ultrasound transducer may be excluded if the spectrum of a given ultrasound transducer obtained from the array includes multiple spikes that satisfy predetermined criteria (e.g., spike width and height; and / or number of spikes), a hallmark of shear wave propagation due to large incident angles. Another example of exclusion criteria may involve a comparison of measured incident angles, which can be measured, for example, by first finding the centroid of a triangular mesh on the outer surface of the skull of a registration mesh segmented from CT, where the shortest distance to each point is along a discrete incident ray pointing from the transducer center to the target, and then calculating the angle between the incident ray of the given ultrasound transducer and the normal to the triangular surface on the skull as a predetermined threshold to exclude ultrasound transducers exceeding a predetermined maximum incident angle.

[0117] In other example implementations, exclusion criteria can be evaluated based on comparisons of received signals with other received signals. In one example implementation, the received signal from a given ultrasound transducer can be compared with received signals from other nearby ultrasound transducers (e.g., adjacent ultrasound transducers within a predetermined distance of the given ultrasound transducer) to assess whether the received signal from the given ultrasound transducer does not meet similarity criteria. In other example implementations, the ultrasound beam of a given ultrasound transducer can be scanned (e.g., electrically or mechanically) within the skull region close to the ultrasound transducer, and multiple received signals obtained during the scan of the skull region can be compared when evaluating exclusion criteria. In this case, if inconsistent spectra are detected among the multiple received signals (e.g., if the comparison metric obtained by processing the multiple received signals does not meet the predetermined similarity criteria), the ultrasound transducer can be excluded. It will be understood that the aforementioned example implementations involving the exclusion of one or more ultrasound transducers based on evaluation criteria can be carried out in the absence of dynamic corrections to determine thermally induced variations that compensate for skull-induced aberrations.

[0118] In one example implementation, the correction for calibrating the transmitted signal delivered to the array of a given ultrasonic transducer can be determined, at least in part, based on the respective corrections determined for one or more ultrasonic transducers located near a given ultrasonic transducer.

[0119] In some example implementations, it may be advantageous to calculate skull thickness and angle of incidence based on multipath in the processing of volumetric image data. If it is determined that the variation in skull thickness (or another metric) exceeds a predetermined threshold, locations within the skull can be excluded during the initial design of the array. It should be noted that high resolution of volumetric image data (e.g., CT scans) (e.g., resolution exceeding 0.082 mm / pixel (Treece et al. 2010)) will provide clearer cortical bone boundaries and result in better thickness calculation fits.

[0120] In some example implementations, the received signal can be processed to achieve intraoperative determination of changes in skull temperature. As shown in the following examples section, the inventors determined that changes in skull resonant frequency have a linear relationship with temperature (see, for example...). Figure 11B Therefore, the resonant frequency can be initially determined or obtained, or obtained from one or more other measures of the received signal that depend on the speed of sound from the skull (not necessarily the skull of the object, for example, based on the average relationship from multiple skull measurements), in relation to temperature, such as... Figure 1B As shown in step 150. As shown in steps 155 and 160, non-therapeutic ultrasound pulses can be delivered to the subject via the array of ultrasound transducers, and an initial value for a metric dependent on the velocity of sound in the skull can be determined by processing the received signal obtained from ultrasound energy reflected from the local cranial region associated with the ultrasound transducer. After delivering focused ultrasound energy (165), an updated metric value can be determined, as shown in steps 170 and 175. The relationship obtained in step 150 can then be used to determine changes in the temperature within the local cranial region associated with the ultrasound transducer based on the change in the metric relative to its previous value, as shown in step 180. This process can be repeated once or multiple times, as shown in step 190, to intermittently and intraoperatively track changes in the local temperature of the skull.

[0121] although Figure 1B Not shown, but the process can be performed for one or more additional ultrasound transducers. For example, when performed on a significant number of ultrasound transducers in an array, such as at least half of the transducers, a metric can be used to generate an (optionally dynamic) thermal image of the skull. It should be understood that this can be implemented... Figure 1B The method described in the text allows for the determination of initial sound velocity-dependent measurements before or after the start of focused ultrasound treatment (thus allowing for the tracking of temperature changes relative to the pre-treatment skull temperature).

[0122] Figure 2 The provided block diagram illustrates an example implementation of a system for performing diagnostic or therapeutic transcranial procedures. Control and processing hardware 300 is operatively connected to the transcranial head assembly 100 via transducer driver electronics / circuit 380.

[0123] Control and processing hardware 300 includes one or more processors 310 (e.g., CPU / microprocessor), bus 305, memory 315 which may include random access memory (RAM) and / or read-only memory (ROM), data acquisition interface 320, display 325, external memory 330, one or more communication interfaces 335, power supply 340, and one or more input / output devices and / or interfaces 345 (e.g., speakers, user input devices such as keyboards, keypads, mice, positioning tracking pens, positioning tracking probes, foot switches, and / or microphones for capturing voice commands).

[0124] Volumetric image data 370 and transducer registration data 375 can be stored in an external database or in the memory 315 or memory 330 of the control processing hardware 300.

[0125] The tracking system 365 may optionally be attached to one or more reference markers 460 of the transcranial head assembly 400, and optionally also have detection by one or more medical instruments or devices attached thereto, for tracking the patient's position and orientation. For example, a stereo tracking system employing two tracking cameras can detect passive or active signals emitted from the reference markers. The transducer driving electronics / circuit 380 may include, for example, but not limited to, Tx / Rx switches, transmit and / or receive beamformers.

[0126] The control and processing hardware 300 can be programmed with programs, subroutines, application programs, or modules 350, including executable instructions that, when executed by one or more processors 310, cause the system to perform one or more methods described in this disclosure. Such instructions can be stored, for example, in memory 315 and / or other memories.

[0127] In the illustrated example embodiment, the transducer control module 355 includes executable instructions for controlling the transducers of the transcranial head assembly 400 to deliver energy to a target location or region based on the registered transducer position and orientation, using volumetric image data, in accordance with transducer registration data 375. For example, the transcranial head assembly 400 may support multiple phased array transducers, and the transducer control module 355 may control applied beamforming (in transmission and / or reception) to deliver one or more focused energy beams to a target region in the far field of the transcranial ultrasound transducer array elements, based on the known position and orientation of the phased array transducers relative to the volumetric image data. The target region may be specified intraoperatively by the user (e.g., via a user interface controlled by the control and processing hardware 300) or according to a pre-established surgical plan.

[0128] The registration module 360 ​​can optionally be used to register volumetric image data 370 to an intraoperative reference frame associated with the tracking system 365. An optional guidance user interface module 362 includes executable instructions for displaying a user interface showing the volumetric image for spatial registration in the image-guided procedure. The registration module 360 ​​can also receive spatial correction information intraoperatively based on a detected spatial offset between the transcranial frame and the patient's head (which may be provided by a subset of distance-sensing transducers) and utilize this spatial correction information to dynamically adjust (e.g., calibrate) the registration between the transducer and the volumetric image data.

[0129] The calibration module 390 includes executable instructions to perform, for example... Figure 1A The method shown is used to determine intraoperative corrections for thermally induced changes in skull-induced aberrations via a control transducer drive circuit 380. The exclusion module 392 includes executable instructions for identifying one or more ultrasound transducers that meet exclusion criteria, for example, according to the method described above. The temperature monitoring module 394 includes executable instructions to perform, for example... Figure 1A The method shown is used to track local skull temperature changes during surgery via a control transducer drive circuit 380.

[0130] although Figure 2 Only one of each component is shown, but the control and processing hardware 300 may include any number of each component. For example, a computer typically contains multiple different data storage media. Furthermore, although bus 305 is depicted as a single connection between all components, it should be understood that bus 305 may represent one or more circuits, devices, or communication channels connecting two or more components. For example, in a personal computer, bus 305 typically includes a motherboard. The control and processing hardware 300 may include more or fewer components than those shown.

[0131] The control and processing hardware 300 can be implemented as one or more physical devices coupled to the processor 310 via one of a plurality of communication channels or interfaces. For example, the control and processing hardware 300 can be implemented using application-specific integrated circuits (ASICs). Alternatively, the control and processing hardware 300 can be implemented as a combination of hardware and software, wherein the software is loaded into the processor from memory or via a network connection.

[0132] Some aspects of this disclosure can be embodied, at least in part, in software that, when executed on a computing system, transforms the computing system into a dedicated computing system capable of performing the methods disclosed herein. That is, the technique can be executed in a computer system or other data processing system in response to its processor, such as a microprocessor, to execute a sequence of instructions contained in memory, such as ROM, volatile RAM, non-volatile memory, cache, disk, and optical disk, or a remote storage device. Furthermore, the instructions can be downloaded to the computing device in compiled and linked form via a data network. Optionally, the logic for performing the above processes can be implemented in another computer and / or machine-readable medium, such as discrete hardware components, as large-scale integrated circuits (LSI), application-specific integrated circuits (ASICs), or firmware, such as electrically erasable programmable read-only memory (EEPROM) and field-programmable gate arrays (FPGAs).

[0133] Computer-readable media can be used to store software and data that, when executed by a data processing system, enables the system to perform various methods. Executable software and data can be stored in various locations, including, for example, ROM, volatile RAM, non-volatile memory, and / or cache. A portion of the software and / or data may be stored in any of these storage devices. Generally, machine-readable media includes any entity that provides information in a machine-accessible form (i.e., stores and / or transmits it) (e.g., a computer, network device, personal digital assistant, manufacturing tool, any device having one or more processors, etc.).

[0134] Examples of computer-readable media include, but are not limited to, recordable and non-recordable media, such as volatile and non-volatile memory devices, read-only memory (ROM), random access memory (RAM), flash memory devices, floppy disks and other removable disks, disk storage media, optical storage media (e.g., CDs, DVDs, etc.). Instructions can be embodied in digital and analog communication links for propagating signals in electrical, optical, acoustic, or other forms, such as carrier waves, infrared signals, digital signals, etc. As used herein, the phrases "computer-readable material" and "computer-readable storage medium" refer to all computer-readable media, except for transient propagation signals themselves.

[0135] Referring now to 3A, a non-limiting and exemplary patient-specific head assembly 400 is shown, worn on a patient's head 50 for performing transcranial diagnostic or therapeutic procedures. The patient-specific head assembly 400 includes a patient-specific frame (support structure) 410 supporting a plurality of transducers 420, conforming to the anatomical contours of at least a portion of the patient's head. Figure 3AThe patient-specific frame 410, shown in the cross-section, mechanically supports the transducer 420 in a pre-selected position and orientation. The transducer 420 can be used to transmit and / or receive energy for brain diagnostic or therapeutic purposes or for positioning on the surface of the skull.

[0136] The patient-specific frame 410 includes multiple attachment interfaces for receiving and supporting the transducer 420. Figure 3A In the example embodiment shown, the attachment interface is configured as a hole (recess) in which the transducer 420 is placed. The transducer 420 can be secured to the patient-specific frame 410 in a variety of different ways, such as, but not limited to, using an attachment mechanism (e.g., via fasteners extending into the patient-specific frame 410, optionally entering a pre-formed hole), or an adhesive, such as glue. Figure 3A In the example embodiment shown, the transducer 420 is remotely coupled to an electronic device via wires or via a flexible printed circuit board 440. The transducer 420 may be removably attached to a patient-specific frame 410.

[0137] Figure 3A The exemplary patient-specific head assembly shown may further include a coupling layer 430 disposed on an inner surface adjacent to the patient-specific frame. The outer surface of the coupling layer 430 contacts the distal surface of the transducer 20, and the inner surface of the coupling layer contacts the patient's head 50, thereby facilitating energy coupling between the transducer and the patient's head within the patient-specific frame. The inclusion of the coupling layer 430, as well as its composition and / or geometry, may depend on the type of transducer 420. For example, if the transducer 420 is an ultrasound transducer, the coupling layer 430 may be an acoustic coupling layer that facilitates sound wave propagation and reduces interface reflections. In one example embodiment, the coupling layer 430 includes an elastic membrane that maintains a liquid layer between the transducer surface and the elastic membrane, thereby enabling coupling with the skin.

[0138] Some transcranial ultrasound arrays have encountered challenges in achieving off-center target ultrasound (e.g., targets more than 2 to 4 cm from the center of the brain) due to the high acoustic impedance of the skull, which prohibits the transmission of longitudinal waves at tilt angles and limits the treatment procedure to targets within the central brain region. (See now for reference.) Figure 3B An exemplary illustration of a transcranial ultrasound transducer array is shown, which addresses the problem by providing an array configured to achieve high-level beam manipulation via the transcranial bone. This is achieved by positioning the transcranial ultrasound transducer array elements relative to the skull such that the far field of each ultrasound beam is located within the brain, and by controlling the timing of the ultrasound pulses emitted by each transducer array element so that the pulses arrive in phase at the desired target.

[0139] Figure 3BThe exemplary transcranial ultrasound transducer array shown includes multiple transcranial ultrasound transducer array elements 500, which are supported relative to the head of the subject by a frame (not shown). Each transcranial ultrasound transducer array element emits its own focused ultrasound beam, as shown by the dashed line. Although Figure 3B The illustration shows only three transducers for illustrative purposes, but for proper focusing, the transcranial device will preferably include more than three elements, as further described below.

[0140] like Figure 3B As shown in the exemplary embodiment, each transcranial ultrasound transducer array element 500 is positioned such that its respective focus is located within the skull. This is in Figure 3C The image shows more clearly a single transcranial ultrasound transducer array element 500 (shown as including an active transducer portion 502 and an optional backing 504) focused onto a focusing region 520 located within the skull 510. By focusing the ultrasound beam within the skull, the near-field region 530 of each beam is positioned within or near the skull, thereby placing the portion of the beam extending within the brain in the far field. This is shown in... Figure 3B In this transcranial ultrasound array, the transcranial ultrasound transducer array elements 500 are focused such that their respective ultrasound beams are dispersed within the brain (shown by cone 545) and propagate in the far field. Unlike other forms of transcranial ultrasound, the individual focuses of the transcranial ultrasound transducer array elements are spatially separated, and the ultrasound beams of the transcranial ultrasound transducer array elements overlap in their respective far fields.

[0141] like Figure 3B As shown, the transcranial ultrasound transducer array elements 500 can be oriented such that their respective ultrasound beams enter the skull at or near normal incidence (e.g., within ±15°). In other exemplary embodiments, the ultrasound beams can be directed towards the skull within ±10°, ±5°, or ±2° of normal incidence. By orienting the transcranial ultrasound transducer array elements 500 in this way and focusing their ultrasound beams within or near the skull, the respective ultrasound beams propagate within the skull as plane waves, thereby reducing losses due to impedance mismatch caused by bone and tissue, and by impedance mismatch caused by bone and water, to the brain.

[0142] Furthermore, by positioning the transcranial ultrasound transducer array element 500 at or near the point of incidence and focusing the ultrasound beam within or near the skull, each ultrasound beam probes a small region of the skull and is thus less susceptible to intracranial heterogeneity, which could lead to scattering due to local impedance mismatch and propagation effects due to local variations in sound velocity. In other words, propagation of each ultrasound beam through a small region of the skull with less variability in skull density and other properties allows for improved correction of bone-induced wave propagation effects.

[0143] Now for reference Figure 3D The timing of the pulses (and / or phase) emitted by each transcranial ultrasound transducer array element 500 is controlled to generate constructive interference at or within a target region located within the brain. In other words, by supporting a sufficient number of transcranial ultrasound transducer array elements 500 around the head, by adjusting the phase of the ultrasound waves generated by the transcranial ultrasound transducer array elements 500, or by adjusting the timing when transmitting short pulses through the transcranial ultrasound transducer array elements 500, the energy from the transcranial ultrasound transducer array elements 500 can be focused onto a desired target location within the brain. This... Figure 3D The case of short-pulse ultrasound is illustrated, in which the timing of the emitted pulses is controlled so that their wavefronts 550A, 550B and 550C are aligned spatially and temporally at a focal point 560.

[0144] like Figure 3B As shown, each transcranial ultrasound transducer array element 500 can be oriented such that all their far-field regions overlap in at least a portion of the intrinsic space of the brain (shown as a focal range or focal region 550), thereby allowing far-field focusing in that region via controlling the timing of ultrasound energy emitted from the transcranial ultrasound transducer array element 500 (e.g., operating the transcranial ultrasound transducer array as a phased array). In some example embodiments, the focal region 550 may be located within a portion of the brain known to contain a target for treatment or imaging, such as a known or suspected tumor, such that the far-field regions overlap at the target region but do not need to overlap elsewhere in the brain.

[0145] although Figures 3B to 3D The transcranial ultrasound transducer array elements shown are illustrated as fixed-focus concave transducers, but it will be understood that one or more (e.g., all) of the transcranial ultrasound transducer array elements 500 may be phased array transducers, hereinafter referred to as subarrays. The term "subarray" is used herein to distinguish the array elements of a transcranial ultrasound transducer array from the elements of a phased array transducer used as array elements of a transcranial ultrasound transducer array. Using phased subarrays for transcranial ultrasound transducer array elements may be advantageous because it allows for selection and / or adjustment of the focus of the transcranial ultrasound transducer array elements without requiring mechanical repositioning of the transcranial ultrasound transducer array elements.

[0146] Figure 4A The process of generating a patient-specific support (scaffold) for supporting transcranial ultrasound transducer array elements is illustrated schematically, as well as the optional process of generating a treatment plan for performing transcranial ultrasound focusing procedures.

[0147] As shown in 600, patient-specific skull features are initially determined using volumetric imaging of the patient. These features are then used to determine the placement of the transcranial ultrasound transducer array elements around the head, as shown in 610. The calculated transcranial ultrasound transducer array element positions are then used to place the elements using a structure that holds the elements, or to fabricate a patient-specific frame (array support structure; support) 610 configured to fit the patient's head. As described below, this patient-specific frame can be manufactured using rapid prototyping, and the support may include attachment interfaces for receiving and supporting the transcranial ultrasound transducer array elements. Finally, on the day of treatment, the array is fixed to the patient for target localization before a typical imaging sequence, followed by computer-aided treatment planning and treatment.

[0148] The patient-specific frame 610 may include multiple attachment interfaces for receiving and supporting the transcranial ultrasound transducer array element 500. For example, the attachment interfaces may be provided as holes (recesses) for placing the transcranial ultrasound transducer array element 500. The transcranial ultrasound transducer array element 500 may be secured to the patient-specific frame 610 in various ways, such as using attachment mechanisms (e.g., via fasteners extending into the patient-specific frame 610, optionally entering pre-formed holes) or adhesives such as glue. The transcranial ultrasound transducer array element may be remotely coupled to electronic devices via wires or via a flexible printed circuit board. The transcranial ultrasound transducer array element 500 may be detachably attached to the patient-specific frame 610.

[0149] The patient-specific head assembly may also include a coupling layer disposed near the inner surface of the patient-specific frame. The outer surface of the coupling layer may contact the distal surface of the transcranial ultrasound transducer array element 500, and the inner surface of the coupling layer contacts the patient's head, thereby facilitating energy coupling between the transducer in the patient-specific frame and the patient's head. The coupling layer may be an acoustic coupling layer that promotes sound wave propagation and reduces reflections at the interface. In one example embodiment, the coupling layer includes an elastic membrane that maintains a liquid layer between the transducer surface and the elastic membrane, thereby enabling coupling with the skin.

[0150] Transcranial ultrasound transducer array elements and their respective attachment interfaces may have unique shapes (i.e., they may be keyed separately) so that a given transcranial ultrasound transducer array element (e.g., its respective housing) uniquely matches its respective attachment interface.

[0151] As described above, the patient-specific frame conforms to the anatomical contours of at least a portion of the patient's head. This conformal frame can be manufactured based on volumetric image data of the patient's head. Figure 4BAn example method for creating a patient-specific framework based on patient-related volumetric image data is illustrated. In steps 610 and 615, volumetric image data of the patient's head is acquired and processed to provide surface data characterizing the anatomical curvature (e.g., skin or bone surfaces) of a portion of the patient's head. Volumetric data can be obtained, for example, by imaging using imaging modalities such as, but not limited to, magnetic resonance (MR) imaging and computed tomography (CT) imaging. The volumetric image data can be obtained based on previously performed imaging procedures.

[0152] Volumetric image data can be processed and segmented to obtain surface data characterizing parts of the patient's skull. For example, technologies such as Mimics can be used. TM This surface segmentation is performed using imaging processing software on software platforms such as Materialise (Belgium). Such software can create 3D models (surface data) of the surface of a portion of a patient's head. Models can be created using known techniques, such as thresholding, region growing, and manual editing. Automated thresholding can be performed to first approximate the skin surface area of ​​the skull, followed by manual editing to obtain a detailed model. Tactile modeling, for example, can be done using modeling software platforms such as PHANTOM. TM A desktop haptic device can be used to further refine the model. Further example methods for image processing and volumetric image data segmentation are disclosed in U.S. Patent No. 8,086,336.

[0153] Subsequently, as shown in step 620, the surface data is used to generate a digital model to determine the placement of the transducer elements around the patient's head. For example, a suitable software platform (such as a software package designer) can be employed. TM This generates a point cloud model based on surface data points. This information can then be used to place transducers, for example, when they are located in supports that allow them to move in desired positions. As shown in step 630, the model is then modified or refined (e.g., updated) to include multiple transducer attachment interfaces for receiving and supporting multiple transcranial ultrasound transducer array elements in preselected positions and orientations relative to the patient's head, and for supporting the transducers to enable transcranial coupling of energy.

[0154] The location and orientation of the transducer attachment interface can be determined as follows. Computer simulations can be used to calculate wave propagation and select the far-field location of the transducer from which it can reach the target location.

[0155] The digital model can be further refined to include one or more additional features, such as, but not limited to, attachment interfaces for attaching one or more reference markers, holes that allow surgery to enter selected areas of the patient’s head when wearing a patient-specific frame (or otherwise placed on or around the patient’s head), markers for identifying reference orientations, and one or more positioning features such as an external handle.

[0156] The updated digital model, including the transducer attachment interface, is then used to fabricate the patient-specific frame, as shown in step 640. For example, the patient-specific frame can be fabricated from the model using 3D printing. In another instance, the model can be used to generate a mold suitable for forming the patient-specific frame, and the mold can then be used to fabricate the patient-specific frame.

[0157] After manufacturing the patient-specific frame, transcranial ultrasound transducer array elements (or transducer array element assemblies or modules) are fixed (attached, glued, etc.) to the transducer attachment interfaces of the respective patient-specific frame, as shown in step 650.

[0158] To enable diagnostic or therapeutic procedures based on preoperative volumetric image data using patient-specific head components, a relationship can be established between the position and orientation of the transcranial ultrasound transducer array elements and the volumetric image data (i.e., so that both can be represented in a common reference frame). Therefore, in step 660, the known position and orientation of the transcranial ultrasound transducer array elements (as specified in the digital model) are spatially registered relative to the volumetric image data, thereby generating transducer registration data characterizing the position and orientation of the transducers relative to the volumetric image data. For example, such transducer registration data may include the spatial coordinates of the transcranial ultrasound transducer array elements in the reference frame of the volumetric data, and vectors identifying their respective orientations. In another example embodiment, the transducer registration data may include coordinate transformations for converting the transcranial ultrasound transducer array elements from a first reference frame to the reference frame of the volumetric image data. Transducer registration data enables the determination of the position and orientation of transcranial ultrasound transducer array elements relative to volumetric image data. For example, it enables the determination of appropriate time and / or phase delays for the transcranial ultrasound transducer array elements to focus the energy beam in overlapping far-field regions, at specific locations or regions within the patient's head. The registration data, volumetric image data, and known position and orientation of the transcranial ultrasound transducer array elements can then be used to generate a treatment plan, as shown in 665.

[0159] In another implementation, registration between the frame and the head and brain can be achieved by using imaging (e.g., MRI, CT, fusion tomography, or X-ray) with a frame placed around the subject's head, allowing transducer location to be determined by imaging visible reference markers within the frame.

[0160] Although the preceding example implementation involves the manufacture and use of a patient-specific frame conforming to the anatomical curvature of the patient's head, it will be understood that this implementation is included to provide an illustrative example of how transcranial ultrasound transducer array elements can be supported.

[0161] According to another example implementation, the transcranial ultrasound transducer array elements can be supported by a support frame that does not have a patient-specific shape, or configured to support multiple transcranial ultrasound transducer array elements, making the transcranial ultrasound transducer array elements adjustable. For example, the transcranial ultrasound transducer array elements can be manually or automatically adjusted relative to the support frame to adjust their position and orientation to match or approximate a position and orientation calculated based on patient-related volumetric image data. For example, the support frame may include one or more motors for changing the position and / or orientation of the transcranial ultrasound transducer array elements. In some example implementations, the transducers can be held in place using rigid or flexible arms, retainers, straps, or other suitable fixation mechanisms.

[0162] While the example embodiments in the above and following examples illustrate a transcranial ultrasound transducer array configuration in which the transcranial ultrasound transducer array elements are focused within the skull, it will be understood that while intracranial focusing may be advantageous in some embodiments, other embodiments may employ a focusing configuration in which one or more transcranial ultrasound transducer array elements have a separate focal point located outside and adjacent to the skull (e.g., adjacent to the inner or outer surface of the skull) such that ultrasound beams extending within the brain overlap in the far-field region.

[0163] While some of the example embodiments described herein illustrate transcranial ultrasound transducer arrays with array elements having the same focal length, it will be understood that the focal lengths between transcranial ultrasound transducer array elements may differ, for example, to account for local variations in skull thickness and / or shape. Furthermore, the size, spatial offset, and / or F-number of the transcranial ultrasound transducer array elements may differ between different elements relative to the skull.

[0164] In some example implementations, the configuration and spatial arrangement of the transcranial ultrasound transducer array elements such that the far field of each ultrasound beam overlaps in a spatial region within the brain, allowing selection of a focused target within an extended focusing region, such as... Figure 3C The extended region is shown. In other example embodiments, the configuration and spatial arrangement of the transcranial ultrasound transducer array elements are such that the spatial overlap of the far-field regions of the ultrasound beams occurs within a spatial region that includes the pre-selected target. In other words, the spatial configuration of the transcranial ultrasound transducer array elements can be selected based on the known target location within the brain.

[0165] Many exemplary embodiments of this disclosure involve using pulsed excitation and controlling the time delay (or phase) of the pulses from the transcranial ultrasound transducer array elements. However, while pulsed excitation may be advantageous for achieving sharp focusing, it is also possible, with appropriate phase control, to achieve continuous wave excitation of the transcranial ultrasound transducer array elements during delivery focused ultrasound therapy to generate a focused area in the far field, particularly for the focal region far from the natural focusing of the transcranial ultrasound transducer array.

[0166] In some example implementations, the transcranial ultrasound transducer array can be operated at two or more frequencies, allowing different subsets of the transcranial ultrasound transducer array elements to operate at different frequencies. For example, dual-frequency excitation has shown promise in preclinical work to date for enhancing acoustic cavitation. As demonstrated in the examples provided below, close focusing and dual-frequency excitation can also be achieved according to this implementation using far-field focusing.

[0167] It will be understood that although this disclosure includes many example embodiments of transcranial ultrasound transducer arrays to be placed around a patient's head, the systems, devices, and methods disclosed herein can be adapted to provide transcranial devices for diagnostic or therapeutic procedures on other parts or components of the body. Support frames for transducers used for far-field focusing can be fabricated based on volumetric image data of other body regions or body parts. For example, a support frame can be fabricated based on volumetric image data of a patient's knee, conforming to the contour of the patient's knee, so as to perform diagnostic or therapeutic procedures on the knee using a transducer supported by the support frame. Similarly, a support frame can be fabricated based on volumetric image data of a patient's spine, conforming to the contour of the patient's spine, so as to perform diagnostic or therapeutic procedures on the spine using a transducer supported by the support frame. Furthermore, while many of the foregoing example embodiments relate to the correction of skull-induced aberrations, the example embodiments described herein can be adapted to the correction of aberrations arising in other bony anatomical regions of the body, such as, but not limited to, the patella or pelvis. Example

[0168] The following embodiments are provided to enable those skilled in the art to understand and practice embodiments of this disclosure. They should not be considered as limitations on the scope of this disclosure, but only as illustrations and representations.

[0169] Example 1: Materials and Methods

[0170] Skull sample:

[0171] In this embodiment, four human ex vivo skull caps fixed in 10% buffered formalin were used. Each skull was mounted in a polycarbonate frame and rinsed with deionized water prior to the experiment, followed by degassing in deionized / deionized water under vacuum for at least two hours. The four skull samples were imaged using a CT scanner as described previously (Pichardo, Sin, and Hynynnen 2011) to obtain skull thickness information for the resonance method and CT-based aberration-corrected density information. The voxel size was 0.625 × 0.625 × 0.625 mm. 3 The image matrix is ​​512×512, and there are 287-307 slices covering the skull cap.

[0172] On-site experiment using a single transducer:

[0173] A schematic diagram of the experimental setup used in this embodiment is shown below. Figure 5 As shown. This study uses a focusing transducer (V389, Olympus, Center Valley, PA, USA) with a fundamental frequency of 0.5MHz, an aperture of 38.1mm, an axial focal length of 55mm, and a lateral half-width of 6.8±0.3mm. An internally fabricated hydrophone with a lead zirconate titanate (PZT) tube, 1mm in diameter and 5mm in height, is mounted 65mm away from the transducer and aligned using an internally fabricated C-shaped support. Its movement is controlled by a three-axis positioning system (PK266-03B-P2) with a two-phase stepper motor. Oriental Motor Co., Ltd., Taito-Ku, Tokyo, Japan; a stepper motor controller (Velmex Inc., East Bloomfield, NY, USA); and an encoder (Quadra-Chek 100, Heidenhain, Schaumburg, IL, USA). Since the normal incident angle of ultrasound propagation is crucial to measurement accuracy (Aarnio et al. 2004, White, Clement, and Hynynen 2006), each skull sample was controlled using a manual rotational locator (Series 481-A, Newport, Irving, CA, USA) and a triaxial Cartesian positioning system (…). The hydrophone was positioned using an Assembliss Series A4000 (Velmex Inc., East Bloomfield, NY, USA) until two separate peaks from the echo signal were visible on an oscilloscope (TDS 3012, Tektronix, Beaverton, OR, USA). The midpoint between the outer and inner surfaces was placed at the transducer's focal point. The hydrophone was moved to at least four landmarks on the skull, visible on CT images. The corresponding coordinates were recorded using a 3-axis locator, assuming the focal coordinates were (0, 0, 10). Two types of measurements were then performed.

[0174] First, a resonance method is employed by having the transducer emit sharp delta-function pulses and using a pulser / receiver (DPR300, JSR Ultrasonics, Pittsford, NY, USA) to receive the pulse echo signal reflected from the target. The transducer's pulse response is characterized by recording the pulse echo signal from the water-air interface.

[0175] Secondly, the hydrophone method was applied by cross-interleaving the time-of-flight of the pulse signals received by the hydrophone in the presence and absence of the skull. This technique has been used as the gold standard for determining skull phase aberration correction in several studies (Hynynen and Sun 1999, Clement and Hynynnen 2002c, Gateau et al. 2010, Hertzberg et al. 2010, Jones et al. 2015). All waveforms were captured by an oscilloscope (sample size: 10). 4 (Sampling frequency: 50MHz), and transmit it to a computer for use with MATLAB. TM Further analysis was conducted using (R2016b, Mathworks, Natick, MA, USA). All measurements were performed in a rubber-lined tank filled with degassed and deionized water.

[0176] Temperature dependence of skull resonance frequency:

[0177] The water temperature is controlled by a heater ( (B, B. Braun Melsungen AG, Melsungen, Germany) Heating and control were performed from 25°C to 42°C in 3°C increments. Each skull sample was immersed in water at the target temperature until a steady-state temperature was reached at each temperature. The phase shift of skull-induced ultrasound waves at selected skull locations was measured using resonance and hydrophone methods.

[0178] Example 2: Data Analysis

[0179] Calculate the angle of incidence and measure skull thickness from CT data:

[0180] To register the skull CT scans with the experimental space, a transformation matrix solved using the method described by Horn (Horn 1987) was applied to the CT data calculated from the marker positions in both the CT and experimental coordinate systems. The accuracy of the registration was also tested by calculating the average distance between the experimental positions of the markers and the new positions transformed from the CT data. In this exemplary measurement, the registration error for all four skulls was 0.6 ± 0.4 mm.

[0181] Following the linear relationship described by Connor et al. (Connor, Clement, and Hynynnen 2002), CT image intensity in Hounsfield units was converted into a density map. In MATLAB... TM Skull segmentation was performed by thresholding density, thus displaying only voxels relevant to the skull. The incident angles of the ultrasound pulses at the outer and inner surfaces of the skull were calculated from triangular mesh skull surface data generated by CT segmentation using a procedure outlined by Jones et al. (Jones, O'Reilly, and Hynynnen 2013). The incident ray, represented by a vector from the transducer center to the target, was defined and discretized into a step size of 0.625 mm quarter-threshold CT voxel resolution. The distance from each point along this ray to the centroid of each triangle on the meshed skull surface was calculated, and the triangle with the shortest distance was found. The incident angle of the skull surface at the triangle closest to the transducer center was determined.

[0182] The “new fixation” method introduced in Treece’s research (Treece et al. 2010) calculates skull thickness from CT data. In short, the density along the incident ray passing through the skull can be modeled as the convolution of density with in-plane and out-of-plane point spread functions (PSFs). The density y at distance x can be expressed as follows (Treece et al. 2010):

[0183] y(x)=y0+(y1-y0)H(x-x0)+(y2-y1)H(x-x1), (6)

[0184] Where y0, y1, and y2 are the densities of water, cortical bone, and trabecular bone, respectively, x0 and x1 are the positions of the outer and inner skull surfaces, and H(x) is a step function. In-plane PSF g i It can be modeled as follows:

[0185]

[0186] Where σ is the fuzzy extension. The out-of-plane PSF can be represented as a rectangular function:

[0187]

[0188] Where 2r represents the degree of uncertainty, calculated from the CT slice thickness and the angle α between the cortical surface normal and the imaging plane, and given by the following equation:

[0189]

[0190] Convolution equations (6) and (7) and (8), fuzzy CT value y blur Represented as:

[0191]

[0192] When r = 0, equation (10) will be modified as follows:

[0193]

[0194] Then the skull thickness d:

[0195] d = (x1 - x0)cos a. (12)

[0196] The CT data were converted from the CT coordinate system to the experimental coordinate system by applying a transformation matrix registered from the skull. A spline interpolation of 100 orders was performed on the line through the skull from the transducer center to the target, which was then fitted using the model of equation (11) to estimate the edge (x0, x1) of the cortical layer, assuming r = 0 (i.e., the cortical layer is orthogonal to the CT imaging plane). During optimization, the density y0 of the water was determined from the histogram of the CT image. y2 (the density of the trabecular bone) was freely determined by the model due to the fact that its density varies at different locations. The in-plane range of the uncertainty σ was unconstrained, and the cortical density y1 was set in the range [2000, 3000].

[0197] CT-based phase correction:

[0198] The analytical methods based on Clement's research (Clement and Hynynnen 2002a) were used to simulate skull-induced phase shifts based on CT-derived skull density, thickness, and orientation relative to the transducer in the experimental setup, similar to the techniques used by Jones & Hynynnen (Jones and Hynynnen 2016) for transcranial passive acoustic imaging. Based on empirical relationships from previous studies (Pichardo et al. 2011), the longitudinal sound velocity within the skull is density-dependent. The time of flight within the skull was determined by calculating the longitudinal sound velocity characteristics along the incident ray between the transducer center and the target, neglecting reflection and refraction effects. Therefore, the time delay caused by the presence of the skull can be expressed as the time-of-flight difference between the skull-crossing and water-crossing cases:

[0199]

[0200] In the formula D n Let be the length of the ray inside the skull. Then the phase shift can be calculated using equation (4).

[0201] Example 3: Results

[0202] In four isolated human skull caps (n Sk1 =276,n Sk2 =151,n Sk3 =148,n Sk4 784 target points were measured on Sk2 (=209). An example of the RF signal reflected back from a target point on Sk2 is shown below. Figure 6A As shown, the normalized spectra before and after deconvolution are as follows: Figure 6B and Figure 6C As shown. By measuring the location of the minimum and applying the frequency difference between adjacent minimums to equation (5), the speed of sound in the skull can be calculated.

[0203] The phase shift calculated based on the resonance method and reflection is combined with Figure 7A The hydrophone method was compared with that used in the study. The average difference between the two methods was 33° ± 26°. The histogram of the phase shift difference is shown below. Figure 7B As shown. In 72.9% of the 784 measurements, the phase shift difference between the two methods was less than 45°, and in 37.1% it was less than 20°. By excluding spots on the outer surface with an incident angle greater than 5°, 80.4% of the 403 measurement points had a phase shift difference of less than 45°, and in 42.9% it was less than 20°, as... Figure 7C and Figure 7D As shown.

[0204] The phase shift, as a function of hydrophone measurements, is calculated from CT-based methods using analytical models, providing insights into the phase shift. Figure 8A and Figure 8CThe CT-based analysis method exhibits systematic bias, as most markers can be observed within the region between 0 and -45°. The average difference between the two methods is 31° ± 20°, decreasing slightly to 29° ± 19° if points with incident angles greater than 5° are excluded. 74.5% of the measures show a phase shift difference of less than 45° between the two methods, and 35.1% show a difference of less than 20°. Figure 8B and Figure 8D . Figure 12 The percentages of skull thickness, incident angle, and phase shift difference were summarized. The resonance method provided results that were generally similar to those of CT-based analysis methods, although the accuracy varied between skulls.

[0205] Additional information shows Figure 9A and Figure 9B The figure shows the percentage of measurement points where the deviation from the three modes is less than a given phase angle difference. The sharp increase indicates a good correlation between the resonance method and the hydrophone method. Figure 9A This illustrates an overall comparison of the resonance method and the CT-based method relative to hydrophones. The resonance method shows a slightly steeper rise in incidence angles less than ° compared to the CT-based method. Specific examples include... Figure 9B As shown. Measurements plotted on each skull based on this bias demonstrate better correlation on Sk2 & Sk3, with 86.1% and 82.4% of the differences being less than 45°, respectively, and 45.0% and 42.0% of the differences being less than 20°, respectively, in contrast to approximately 67% of the points on Sk1 and Sk4 with biases less than 45° and approximately 35% with biases less than 20°.

[0206] Figure 10A and Figure 10B This paper compares the resonance / CT method with the hydrophone method based on the calculated mean time delay induced by the skull and the SoS in the skull. The results show that the resonance method produces more accurate time delay and sound velocity estimates than the CT-based method.

[0207] Information on the skull phase shift difference between the resonance / CT method and the hydrophone method allows for estimation of the reduction in transcranial peak sound pressure. For a phase array with N elements, assuming that the peak amplitude of the hydrophone phase correction through each element is the same and normalized to 1, the peak pressure amplitude at the focal point will be reduced by a percentage (Clement and Hynynnen 2002a):

[0208]

[0209] (13) Where ΔP is the pressure loss and P0 is the peak pressure at the focal point of the hydrophone method. This is the absolute value of the phase error caused by inaccurate prediction of skull phase shift from resonance / CT-based analysis methods. When using the resonance method, the peak pressure reductions were 6.7%, 4.4%, 5.6%, and 10.8%, respectively, in contrast to the smaller pressure reductions of 2.4%, 5.5%, 4.9%, and 3.5% observed using the CT method on skull Sk1, Sk2, Sk3, and Sk4. Skull phase shift measurements were performed using both resonance and hydrophone methods at temperatures ranging from 25°C to 42°C. Figure 11A The average phase transition of all four skull samples between room temperature and 42°C is shown as a function of temperature at 0.5 MHz. The resonance method yields a phase transition of 2.65° per °C, slightly higher than the 2.05° given by the hydrophone method. The change in the average resonant frequency of the skull is proportional to the change in temperature, with a negative coefficient, as shown in the figure. Figure 11B As shown.

[0210] Phase shifts at each point were measured using resonance and hydrophone methods at elevated temperatures. No sharp decrease in accuracy was observed during temperature elevation. Accuracy obtained from each skull and all four skulls at each temperature was averaged. The average accuracy within a 17°C temperature difference was 78% ± 9% for all measured points.

[0211] Example 4: Analysis

[0212] This study explored factors that might improve the accuracy of the resonance method in determining skull-induced ultrasound phase shifts. The results showed that when the resonance method was compared with the hydrophone method, all measurement points (n) 总 In the model (=784), approximately 73% and 37% of the deviations are less than 45° and 20°, respectively, representing increases of nearly 65% ​​and 30% compared to previous studies (Aarnio et al. 2005). The average difference in phase shift between the two models is 30.5°, approximately 15° smaller than Aarnio's study (Aarnio et al. 2005). This reduced difference indicates that the modified resonance method has higher accuracy in phase aberration correction.

[0213] The improved accuracy likely stems first from the experimental configuration where the transducer's focus is concentrated within the skull. This benefits from a smaller field size and larger aperture, resulting in less interference with skull geometry measurements and a higher signal-to-noise ratio (SNR) compared to earlier studies (Aarnio et al. 2004). Secondly, the incident angle of the ultrasound pulse plays a crucial role in measurement accuracy. It has been shown that the spectrum deteriorates rapidly with increasing incident angle (Aarnio et al. 2004, White et al. 2006), leading to additional difficulties in detecting resonant frequencies. By eliminating measurement points with incident angles ≥5° (n = 403), approximately 80% of the measurements exhibited a bias of 45° or less. Comparing the SoS in the skull predicted by the two methods, the resonance method provides 2310 ± 180 m / s, which is about 1.3% lower than the average sound velocity of 2340 ± 170 m / s given by the hydrophone method, and is in contrast to the 5.8% higher value in the previous study (Aarnio et al. 2005).

[0214] The skull thickness calculated from CT data also affects the accuracy and practicality of the method. In this study, the resolution of the CT images (0.625 mm) is close to one-quarter of the transducer center frequency wavelength (0.75 mm), meaning that a one-voxel difference can lead to a phase change of almost 45°. At a given resolution, it is necessary to interpolate the CT data and fit it to an optimized model to provide an accurate skull thickness estimate. Two algorithms, “Half-Max” and “New Fixed”, described in Treece’s study (Treece et al. 2010), have been tested. “Half-Max” provides better thickness estimates on Sk2 and Sk4, but not on Sk1 & Sk3 (where the skull is thinner). Figure 12 The accuracy of the "newly fixed" method in assessing skull thickness was relatively poor. However, the "newly fixed" method was more accurate in cases of thin skulls. This result is consistent with simulations in the Treece study, where the "semi-maximal" method tends to overestimate cortical bone thickness less than 2.2 mm, especially at lower CT resolutions, leading to a systematic bias in the phase shift calculation by the resonance method. In this study, the cortical bone thickness on Sk1 & Sk3 was less than 2.2 mm, which explains why the "newly fixed" method provided a better thickness estimate. Ultimately, the "newly fixed" technique was adopted in this study.

[0215] The results of this experiment have confirmed that using a lower frequency transducer helps improve measurement accuracy from 65% (at 0.9 MHz) (Aarnio et al. 2005) to 73% (at 0.5 MHz), resulting in lower attenuation through the skull at 0.5 MHz (Sun and Hynynnen 1998) and increased SNR in the data. Furthermore, it is less affected by the angle of incidence. However, there is a trade-off between the low center frequency and the wide bandwidth. The narrower bandwidth resulting from the lower frequency increases the difficulty of determining the resonant frequencies on the thin skull. The transducer bandwidth in this study is in the range of [0.3, 0.8] MHz, which is much narrower than the range of [0.6, 1.74] MHz in previous work (Aarnio et al. 2005), making it difficult to measure the resonant frequencies of Sk1 & Sk3.

[0216] Although the accuracy of the resonance method has been shown to improve, some outliers still exist outside the constructive interference region, even under normal incidence conditions, such as... Figure 7C As shown. Several factors can lead to errors when using the resonance method. First, by comparing the "newly fixed" fit in skull thickness calculation with CT density features along the ultrasound propagation path at locations with larger errors, it was found that the "newly fixed" method (Treece et al. 2010) sometimes fails to find the correct boundary of the cortical bone when using a thick skull, resulting in inaccurate phase shift calculations. This phenomenon is consistent with Treece's simulations, where the "newly fixed" fit tends to give a slightly larger error than the true value when the cortical bone thickness exceeds 3.5 mm, but it is less sensitive to overall cortical bone thickness compared to other fitting methods.

[0217] Furthermore, the heterogeneity of the skull also introduces errors into the calculations. Careful examination of CT slices near outliers revealed inconsistencies in skull structure within the focal region at some locations (FWHM: 6.8 ± 0.3 mm), showing a sharp decrease in trabecular density. Since the phase shift information provided by the resonance method is a combination of multiple reflection paths, large variations in bone density can cause significant errors when compared to hydrophone-based and CT-based analysis methods that utilize simplified skull structures based on single-path propagation.

[0218] Therefore, it was determined that, in order to further improve the accuracy of the resonance method, a smaller focusing transducer could be used to avoid large deviations from the skull structure and to maintain the validity of the flat skull surface assumption.

[0219] Direct comparisons have been presented between the resonance method and other non-invasive methods, such as CT-based analytical models. Overall, compared to the gold standard method, the resonance method provides slightly better predictions of skull phase shifts based on phase difference distributions as a CT-based analytical model, such as... Figure 9AAs shown. Figure 7A and Figure 7C As shown, the phase shift calculated by resonance appears to be unbiased along the main diagonal, providing better accuracy than CT-based analysis methods, where it is possible to... Figure 8A and Figure 8C The phase lag shown indicates a system shift. In the CT-based analytical model, although spline interpolation has been performed along the incident rays through the skull, and the SoS is density-dependent based on the density features given by the fitting (Pichardo et al. 2011), the boundaries of the cortical bone, limited by low CT imaging resolution, may still be uncertain, and therefore the thickness is overestimated, especially when the thickness is small, similar to the results given by the 'half-maximal' method (Treece et al. 2010). Furthermore, parameters such as bone longitudinal SoS used in the analytical model are empirical, and the skull is simplified to a multi-layer model, resulting in skull phase shift predictions similar to those of resonance methods.

[0220] As mentioned above, previous work has shown that the phase shift change of the skull measured by hydrophones as a function of temperature follows a linear fit, with a slow increase of 0.29° phase per °C, resulting in a total phase shift change of less than 14° when the temperature increases from 22 °C to 50 °C (Clement and Hynynnen 2002a). Therefore, it was concluded that increased temperature does not significantly affect the phase shift change, and thus the phase shift measured at room temperature can be applied to skull phase correction at body temperature. However, temperature control was not performed in this study. Skull samples were heated in a separate water tank and transferred to the experimental setup when the temperature reached a set value. Once the skull was placed in room temperature water, thermal diffusion occurred, reducing the actual temperature of the skull measured. In our study, modifications were made to allow for temperature control and skull phase shift measurements in the same experimental setup. Both the resonance (2.65° / °C) and hydrophone methods (2.05° / °C) were found to produce higher slopes than in previous studies (see [link to previous study]). Figure 11A Therefore, compensating for the phase shift caused by thermal deposition may be beneficial, since a 10°C increase in temperature from high-intensity ultrasonic treatment results in a phase shift of approximately 20°C, and approximately 39% of the phase correction shifts out of the constructive interference region.

[0221] Secondly, this result ( Figure 11A This indicates that, overall, the resonance method provides a higher slope than the hydrophone method. The resonance method relies on pulse echo signals from multiple paths and therefore, as temperatures rise, more variation is expected based on skull density and incident angle, unlike hydrophone measurements based on single-path propagation.

[0222] Third, it has been found that, compared with the hydrophone method, the resonance method provides a better linear fit to the phase shift dependence of temperature changes in all tested skulls. Last but not least, the accuracy of the resonance method in determining the skull phase shift during temperature rise is summarized compared with the standard hydrophone method. No significant trend of decreasing accuracy with increasing temperature was observed in the skull, and the average accuracy was maintained at 78% ± 9% (n = 110).

[0223] Specific embodiments described above have been illustrated by way of example, and it should be understood that these embodiments may be readily modified and substituted in various ways. It should be further understood that the claims are not intended to limit to the specific forms disclosed, but rather to cover all modifications, equivalents, and substitutions falling within the spirit and scope of this disclosure.

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Claims

1. An intracranial focused ultrasound therapy system, comprising: Array of ultrasonic transducers; A transducer drive circuit, which is operatively coupled to an array of ultrasonic transducers; and A control and processing circuit, operably coupled to the transducer drive circuit, includes at least one processor and an associated memory storing instructions executable by the at least one processor to perform the following operations: After initiating the delivery of focused ultrasound to the object using the array of ultrasound transducers in a focused ultrasound therapy procedure: a) The array of ultrasonic transducers is used to transmit non-therapeutic ultrasonic pulses and receive reflected ultrasonic pulses reflected from the surface of the skull in a local skull region adjacent to the ultrasonic transducer, thereby obtaining a received signal. b) Determine a correction for calibrating the treatment transmission signal delivered to the ultrasound transducer during subsequent focused ultrasound treatment, wherein the correction is adapted to reduce cranial evoked aberrations associated with the local cranial region, wherein the correction is determined by processing the received signal and employing a cranial thickness estimate associated with the local cranial region, and wherein the cranial thickness estimate is obtained based on previously measured object-related volumetric image data; and c) Controlling the transducer drive circuit such that, during focused ultrasound treatment followed by delivery to the object in the focused ultrasound treatment procedure, the correction is applied to the transmission transducer provided to the ultrasound transducer; and d) Repeat steps a) through c) once or more during the focused ultrasound treatment procedure to intermittently and intraoperatively recalculate the correction and control the transducer drive circuit so that the correction is applied during subsequent focused ultrasound delivery and thereby maintains aberration reduction, although local thermally induced changes in the velocity of sound in the local cranial region are caused by spatially uneven increases in skull temperature due to intraoperative intracranial heating.

2. The system of claim 1, wherein the operation includes performing steps a)-c) to determine the respective calibrations of at least a subset of the ultrasonic transducers of the array.

3. The system of claim 2, wherein the operation includes: The received signal is processed to determine one or more metrics associated with the received signal that meet exclusion criteria, and The ultrasound transducer is not used during subsequent delivery of focused ultrasound therapy via the array.

4. The system of claim 3, wherein the evaluation of the exclusion criterion depends on the signal-to-noise ratio of the received signal.

5. The system of claim 3, wherein the evaluation of the exclusion criterion is based on the presence of one or more spikes in the spectrum of the received signal.

6. The system of claim 3, wherein the exclusion criterion is based on a comparison of the received signal with one or more received signals obtained from one or more adjacent ultrasonic transducers.

7. The system of claim 3, wherein the exclusion criterion is based on a comparison of the received signal with one or more received signals obtained by scanning the ultrasonic transducer.

8. The system of claim 3, wherein the exclusion criterion is based on the measured incident angle of the ultrasonic transducer.

9. The system of any one of claims 1 to 8, wherein the operation comprises: Further calibrations for the additional ultrasonic transducers are generated based on the calibrations of one or more adjacent ultrasonic transducers.

10. The system of claim 1, wherein the operation includes performing steps a) to c) on all the ultrasonic transducers of the array.

11. The system of any one of claims 1 to 10, wherein, in step b), the received signal is processed in the frequency domain to identify a resonant frequency associated with the local cranial region, and wherein, in calculating the correction, the resonant frequency difference and the cranial thickness estimate are used.

12. The system of any one of claims 1 to 10, wherein, in step b), the received signal is processed in the time domain using a pulse-echo method to determine the time delay associated with propagation through the local cranial region, and wherein, in calculating the correction, the time delay and the cranial thickness estimate are employed.

13. The system of any one of claims 1 to 7, wherein, in step b), the correction is calculated using an angle of incidence relative to the external skull surface corresponding to the local skull region, which is associated with the ultrasonic transducer.

14. The system of claim 13, wherein the angle of incidence is determined by registration between a reference frame associated with the volumetric image data and an intraoperative reference frame.

15. The system of claim 13, wherein the array of ultrasound transducers is supported by a patient-specific head assembly, wherein an incident angle relative to the external skull surface associated with the ultrasound transducers of the array is pre-configured based on the orientation of the ultrasound transducers relative to the patient-specific head assembly.

16. The system of claim 13, wherein the incident angle associated with the ultrasound transducer is changed intraoperatively to maximize the received signal to achieve normal incidence.

17. The system of claim 16, wherein the incident angle is changed by manipulating the non-therapeutic ultrasound pulse.

18. The system of claim 17, wherein the ultrasonic transducer is a phased array ultrasonic transducer, and wherein the incident angle is changed by electron beam manipulation.

19. The system of claim 17, wherein the ultrasonic transducer is a unitary ultrasonic transducer, and wherein the incident angle can be mechanically changed.

20. The system of any one of claims 1 to 19, wherein the non-therapeutic ultrasound pulse is focused on the local cranial region.

21. The system of any one of claims 1 to 20, wherein the center frequency of the non-therapeutic ultrasound pulse is located at 400 to 600 kHz.

22. A non-temporary computer-readable storage medium storing instructions, when executed by one or more processors in an intracranial ultrasound therapy system comprising an array of ultrasound transducers and associated transducer drive circuitry, to cause the system to perform operations including: a) The array of ultrasonic transducers is used to transmit non-therapeutic ultrasonic pulses and receive reflected ultrasonic pulses reflected from the surface of the skull in a local skull region adjacent to the ultrasonic transducer, thereby obtaining a received signal. b) Determine a correction for calibrating the treatment transmission signal delivered to the ultrasound transducer during subsequent focused ultrasound treatment, wherein the correction is adapted to reduce cranial evoked aberrations associated with the local cranial region, wherein the correction is determined by processing the received signal and employing a cranial thickness estimate associated with the local cranial region, and wherein the cranial thickness estimate is obtained based on previously measured object-related volumetric image data; and c) Configure the transducer drive circuit such that, when the focused ultrasound is subsequently delivered to the object during the focused ultrasound treatment procedure, the correction is applied to the transmission signal provided to the ultrasound transducer; and d) Repeat steps a) through c) once or more during the focused ultrasound treatment procedure to intermittently and intraoperatively recalculate the correction and control the transducer drive circuit so that the correction is applied during subsequent focused ultrasound delivery and thereby maintains aberration reduction, although local thermally induced changes in the velocity of sound in the local cranial region are caused by spatially uneven increases in skull temperature due to intraoperative intracranial heating.

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